Glioblastomas are the most common and malignant brain tumor in adults and account for over 50% of all gliomas. Current standard of care combines surgical resection with temozolomide chemotherapy and radiotherapy, but 5 year survival rates remain less than 20%. There is a critical need for new therapies that increase efficacy without increasing toxicity. One therapeutic target can be found in the aberrant metabolism that is a hallmark of cancer. We have previously used an intracranial syngeneic immunocompetent mouse model of malignant glioma to demonstrate that targeting metabolism using a ketogenic diet reduced tumor burden and increased survival. The ketogenic diet is a high fat, low carbohydrate plus protein diet used for the treatment of refractory pediatric epilepsy. Mice maintained on a ketogenic diet (KetoCal®, Nutricia North America, Gaithersburg, MD) had a reduction in inflammation and peri-tumoral edema, prompting us to question the effects of the ketogenic diet on the infiltration and the functionality of glioblastoma-reactive immune cells. Immune cells were isolated from malignant gliomas from mice treated with either the ketogenic diet or a standard diet. Glioblastoma-specific immune cells were tested for functionality via cytokine production, capacity for cytotoxicity, and amount of infiltration. We found the ketogenic diet significantly decreased expression of the inhibitory receptors CTLA4 and PD-1 on tumor-infiltrating T cells, and coincided with a reduction in inhibitory ligand expression on the tumor. Moreover, this reduced T cell tolerance at the tumor site allowed CD8+ T cells to produce IFNγ and IL-2, and regain cytotoxic functions. Additionally, the ketogenic diet caused a reduction in immunosuppressive cytokine production via regulatory T cells. Innate immune responses to the tumor were also altered in mice maintained on the ketogenic diet, as natural killer cells infiltrating the tumor were able to produce more IFNγ and TNF in response to GL261-luc2 cells in vitro. Overall, the ketogenic diet may be an attractive adjuvant therapy to overcome several immune escape mechanisms in gliomas by decreasing regulatory T cell suppression of effector T cells and increasing CD8+ T cell killing and cytokine production, ultimately leading to increased tumor immune mediated rejection.
Citation Format: John L. Johnson, Eric Woolf, Danielle M. Lussier, Ken S. Brooks, Joseph N. Blattman, Adrienne C. Scheck. Ketogenic diet enhances immunity to glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B73.
- ©2015 American Association for Cancer Research.